Machine readable medium embodying instructions for citrate anticoagulation system for extracorporeal blood treatments

ABSTRACT

A machine-readable medium with instructions for pumping blood from a patient&#39;s blood stream into an access line, introducing an anticoagulant solution into the pumped blood, filtering the pumped blood and delivering it to a return line, introducing a substitution fluid into the pumped blood, introducing a calcium and magnesium solution into the blood traveling through the return line, and returning the blood back to the patient&#39;s blood stream.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a division application of U.S. patent applicationSer. No. 13/359,109, filed Jan. 26, 2012, now U.S. Pat. No. 8,529,486,which is a division application of U.S. patent application Ser. No.11/602,827, filed Nov. 21, 2006, now U.S. Pat. No. 8,105,258, whichclaims benefit of priority from U.S. Provisional Patent Application Ser.No. 60/739,086, filed Nov. 22, 2005. U.S. patent application Ser. No.11/602,827 is also a continuation-in-part of related U.S. patentapplication Ser. No. 10/742,137, filed Dec. 19, 2003, now U.S. Pat. No.7,186,420, which is a continuation-in-part of U.S. patent applicationSer. No. 09/959,543, filed Oct. 23, 2001, now U.S. Pat. No. 6,743,191,which is a Section 371 filing of PCT/EP00/03583, filed Apr. 20, 2000,which claims priority to EP 99201302.9, filed Apr. 26, 1999, the entirecontents of which are all herein incorporated by reference in theirentirety.

FIELD OF THE INVENTION

The invention relates generally to extracorporeal blood treatmentsystems. More particularly, the invention relates to a citrateanticoagulation treatment for an extracorporeal blood treatment systemcapable of introducing various solutions into the blood to assist in thefiltering of the blood.

DESCRIPTION OF THE RELATED ART

Extracorporeal blood treatment is a therapy that is widely used forcritically ill patients. Many of these patients suffer from acute renalfailure and are treated with various forms of hemofiltration, such asContinuous Renal-Replacement Therapy (CRRT), Continuous Veno-VenousHemofiltration (CVVH), Continuous Arterio-Venous Hemofiltration (CAVH),and Continuous Veno-Arterial Hemofiltration (CVAH).

Another form of renal replacement therapy that can be used for patientswith renal failure in Intensive Care Units (ICU's) is hemodialysis. Purehemofiltration, as a renal-replacement therapy in an ICU, can becombined with hemodialysis to provide aContinuous-Veno-Venous-Hemo-DiaFiltration (usually abbreviated as CVVHDor CVVHDF) or a Continuous-Arterio-Venous-Hemo-DiaFiltration (usuallyabbreviated as CAVHD or CAVHDF). The addition of hemodialysis to ahemofiltration therapy allows the infusion of a hemodialysis fluid, suchas a dialysate fluid, making such combined therapy forms more complexthan pure hemofiltration. Hemodialysis usually can only be applied for afew hours per day, and as such, is much less effective than purehemofiltration.

Typically, an artificial kidney is used for extracorporeal treatments.This kidney may be formed of hollow-fibers or of plates, and isconnected to a patient's bloodstream by an extracorporeal circuit. InCVVH(D) the supply from and return to the blood of the patient is madevia two venous accesses, using a blood pump to provide the driving forcefor the transport of blood from the patient into the artificial kidneyand back to the patient. In CAVH(D), the access which provides thesupply of blood to the artificial kidney is made via an artery and thereturn of the blood to the patient is made via a venous access. In mostcases, blood pumps are generally not used because the arterial bloodpressure is used to provide the driving force for the transport ofblood, which implies that the blood flow rate directly varies with theblood pressure. Because of better control of blood flow, no risk ofarterial catheter-related complications, and higher treatmentefficiency, CVVH is a preferred renal replacement therapy in ICU's overCAVH.

In CVVH, the patient's blood is passed through the artificial kidneyover a semipermeable membrane. The semipermeable membrane selectivelyallows plasma water and matter in the blood to cross the membrane fromthe blood compartment into the filtrate compartment, mimicking thenatural filtering function of a kidney. This leads to a considerableloss of fluid from the blood, which is removed as the filtrate in theartificial kidney. Every liter of filtrate fluid that is removed in theartificial kidney, contains a large fraction of the molecules that aredissolved in the plasma, like urea, creatinine, phosphate, potassium,sodium, glucose, amino acids, water-soluble vitamins, magnesium,calcium, sodium, and other ions, and trace elements. The fraction of themolecules that passes the semipermeable membrane depends mainly on thephysico-chemical characteristics of the molecules and the membrane. Inorder to keep the blood volume of the patient at a desired (constant)level, a substitution infusion fluid is added to the blood stream in theextracorporeal circuit, after is has passed through the artificialkidney and before it re-enters the patient's vein.

In a normal CVVH procedure, approximately 50 liters of filtrate areremoved per 24 hours, and approximately the same amount of substitutioninfusion fluid is added into the return of blood side of theextracorporeal circuit. The substitution infusion fluid commonly used isconventional infusion fluid comprising a physiological saline solutiongenerally only containing about 140 mmol/L of sodium ions, 1.6 mmol/L ofcalcium ions, 0.75 mmol/L of magnesium ions, 36 mmol/L of bicarbonateions, and 110 mmol/L of chloride ions. All forms of hemodialysis orhemodiafiltration therapies are characteristically different from purehemofiltration by the use of a dialysate fluid flow along thesemipermeable membrane side opposite to the blood side.

In order to prevent coagulation of the blood during hemofiltration,usually an anticoagulant is added to the blood in the extracorporealcircuit before it enters the artificial kidney. In the past, heparin orfractionated heparin was often used for this purpose. A drawback of theuse of heparin, however, is that this use leads to systemicanticoagulation (i.e., anticoagulation of all blood including thatwithin the patient), giving rise to the risk of the occurrence ofserious bleeding complications, particularly in seriously ill patients.

Instead of heparin, citrate ions can be used as an anticoagulant forhemodialysis. Citrate ions, usually added in the form of trisodiumcitrate, are believed to bind free calcium ions in the blood, which havea pivotal role in the coagulation cascade. Citrate ions, added to theblood into the extracorporeal circuit before it enters the artificialkidney, are only active as an anticoagulant in the extracorporealcircuit, whereby the risk of bleeding complications due to systemicanticoagulation is avoided. When citrate ions are applied duringhemodialysis forms of treatment, a calcium-and-magnesium-freesubstitution fluid or dialysate is required. Therefore, the applicationof citrate ions during hemodialysis is more complex than during purehemofiltration.

Citrate ions are mainly metabolized in skeletal muscle and liver tissue.Only in cases of severe hepatic failure combined with severe shock, orof certain (rare) metabolic diseases, the metabolism of citrate may runshort, leading to too high citrate concentrations in the systemic bloodcirculation, which on its turn may endanger the patient. Accordingly,citrate ions are an attractive anticoagulant for use in purehemofiltration procedures, especially for use in CVVH treatment in ICUpatients.

Because citrate ions bind to positively charged metal ions like calcium,magnesium, iron, zinc, copper, and manganese, these ions are partlyremoved in the artificial kidney, leading to a net removal of calciumand magnesium ions and other metal ions from the patient's blood. As aresult, hypocalcemia and/or hypomagnesemia and/or shortages of othermetal ions may be induced in the patient that can lead tolife-threatening complications. The process of hemofiltration, alsoinduces a net removal of phosphate and potassium ions, trace elements,water-soluble vitamins, amino acids and of glucose in the artificialkidney. This may lead to significant degrees of hypovolemia,hypophosphatemia, hypokalemia, with a risk of deteriorating thepatient's condition. Hypophosphatemia may also induce life-threateningcomplications in the patient.

Therefore, there is a need in the art for an extracorporeal bloodtreatment system that is capable of introducing an appropriate volume ofsubstitution infusion fluid per unit of time and an appropriate volumeof anticoagulation solution per unit of time to prevent complicationsfrom occurring to the patient.

SUMMARY OF THE INVENTION

One embodiment of the invention provides a hemofiltration system havingan access line configured to carry blood from a patient's blood stream,a first pump configured to pump the blood through the access line, asecond pump for introducing an anticoagulant solution into the bloodtraveling through the access line, a filter for filtering the bloodtraveling through the access line, a third pump for introducing asubstitution fluid into the blood, a fourth pump for introducing acalcium and magnesium solution into the blood, a return line configuredto carry blood back to the patient's blood stream, and a processing unitfor controlling a flow rate for the first pump, the second pump, thethird pump, and the fourth pump, the fourth pump being coupled to thereturn line. The third pump may be coupled to the access line or thereturn line.

Another embodiment of the invention provides a hemofiltration method forpumping blood from a patient's blood stream into an access line,introducing an anticoagulant solution into the pumped blood, filteringthe pumped blood, delivering the pumped blood from the filtering step toa return line, introducing a substitution fluid into the pumped blood,introducing a calcium and magnesium solution into the blood travelingthrough the return line, and returning the blood back to the patient'sblood stream. The substitution fluid may be introduced to the accessline or the return line.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates an extracorporeal blood treatment system according toone embodiment of the invention.

FIG. 2 illustrates an extracorporeal blood treatment system according toone embodiment of the invention.

FIG. 3 illustrates an extracorporeal blood treatment system thatintroduces a substitution infusion fluid to the access line inconjunction with the return line according to one embodiment of theinvention.

FIG. 4 illustrates an extracorporeal blood treatment system that infusesan anticoagulant before and after the blood pump on the access line andintroduces a substitution infusion fluid to the access line inconjunction with the return line according to one embodiment of theinvention.

FIG. 5 illustrates an extracorporeal blood treatment system with amonitor system according to one embodiment of the invention.

FIG. 6 illustrates a simplified block diagram of a control system thatregulates, controls, and monitors the operations of the extracorporealblood treatment system according to one embodiment of the invention.

DETAILED DESCRIPTION

Methods and systems that implement the embodiments of the variousfeatures of the invention will now be described with reference to thedrawings. The drawings and the associated descriptions are provided toillustrate embodiments of the invention and not to limit the scope ofthe invention. Reference in the specification to “one embodiment” or “anembodiment” is intended to indicate that a particular feature,structure, or characteristic described in connection with the embodimentis included in at least an embodiment of the invention. The appearancesof the phrase “in one embodiment” or “an embodiment” in various placesin the specification are not necessarily all referring to the sameembodiment. Throughout the drawings, reference numbers are re-used toindicate correspondence between referenced elements.

FIGS. 1-4 illustrate various embodiments of the invention for anextracorporeal blood treatment system. In this system, blood isextracted from a vein of a patient and transported to an artificialkidney 60 via the access line 1 of an extracorporeal circuit by thedriving force of a blood pump 14. In one embodiment, a pressuremonitoring system, shown in FIGS. 4 as 19 and 21, is connected to theaccess line 1 pre- and post-blood pump 14 to control thedepressurization created by the pumping system of blood from the patientand pressurization created by the pump 14 before the artificial kidney60. The connections or inlet ports (not shown) for the pressuremonitoring system 19 and 21 may include a closing system, such as avalve, a mechanical clamp, or a male Luer-lock connector.

An anticoagulant solution, such as a citrate or heparin anticoagulationsolution, can be infused from a reservoir, shown in FIG. 4 as 25 or 30,to the access line 1 of the extra-corporeal circuit. In One embodiment,the anticoagulant solution can be pumped 24 to the access line 1pre-blood pump 14 at inlet port 32. As shown in FIG. 1, theanticoagulant solution can also be infused to the access line 1post-blood pump 14 at inlet port 10. Both inlet ports 10 and 32 maycontain a closing system, such as a valve, a mechanical clamp, orLuer-lock connectors. In one embodiment, the anticoagulant solutionpasses through a drip chamber or air trap (device not shown) beforebeing infused into the access line 1 of the extra-corporal circuit. Theanticoagulant line can be color coded black.

By using the citrate anticoagulation infusion fluid in an extracorporealblood treatment system, the blood is effectively anticoagulated withinthe extracorporeal circuit and not within the systemic circulation ofthe patient and the concentrations of sodium, potassium, calcium,magnesium, and bicarbonate ions remain substantially within ranges ofwhich it is accepted that they do not lead to unacceptable risk ofcomplications within the patient. This citrate anticoagulant solutioncould be used in any appropriate extracorporeal blood treatment and isespecially useful during all kinds of pure hemofiltration procedures incombination with the matching substitution infusion fluids according tothe invention.

In one exemplary embodiment, the citrate anticoagulation solution forpure hemofiltration treatment can be an aqueous solution comprisingabout 38 mmol/L of citric acid and about 212 mmol/L of trisodiumcitrate. This citrate anticoagulation solution can be used during pureCVVH in combination with a matching substitution infusion fluidcomprising about 118 mmol/L of sodium ions, about 2.3 mmol/L of calciumions, about 2.6 mmol/L of potassium ions, about 0.8 mmol/L of phosphateions, about 0.9 mmol/L of magnesium ions, about 6.5 mmol/L of glucose,less than about 5.5 mmol/L of acetic acid, and chloride ions to keepelectrochemical balance. Moreover, it may be desirable to add about 0.0mmol/L to about 5.5 mmol/L of acetate ions to prevent the formation ofcalcium phosphate sedimentation in the one part substitution infusionfluid. In other embodiments, for example, glucose and/or acetic acidand/or phosphate may be omitted, as well as concentrations of otheringredients can be adjusted up or down as necessary.

The mixture of blood with anticoagulation solution travels down theaccess line of the extra-corporeal circuit. At the end of the accessline 1 are one or more connectors 40, such as male and female ISOconnectors, that couple the access line 1 to the artificial kidney 60.In the artificial kidney 60, the blood can be filtered through asemi-permeable membrane 5. Fluids contained in the blood and/orintroduced from inlet dialysate port 18 are drained from the filtratecompartment 6 of the artificial kidney 60 via connecting tubing 7 to acollection reservoir 9. The tubing 7 is coupled to the artificial kidney60 using one or more connectors 54, such as male and female Luer-Lockconnectors. A pump 8 moves the filtrate into the collection reservoir 9and generates an effluent flow rate.

As shown in FIG. 4, the connecting tubing 7 may be coupled to a pressuremonitoring system 22 for controlling filtrate pressurization. Also, theconnecting tubing 7 is connected to a blood leak detector chamber 36 forcontrolling leakage of red blood cells through the membrane 5 of theartificial kidney 60. In one embodiment, the connecting tubing 7 mayinclude a closing system, such as a mechanical clamp, between the pump 8and the collection reservoir 9. The connecting tubing 7 may be connectedto the collection reservoir 9 using connectors, such as male and femaleLuer-lock connectors.

A retentate blood is transported back from a retentate compartment 4 ofthe artificial kidney 60 to the patient's blood stream via the returnline 2 of the extracorporeal circuit, after passage through an air trap3. The artificial kidney 60 is coupled to the return line 2 using one ormore connectors 42, such as male and female ISO connectors. The air trap3 serves to remove all air bubbles from the blood before it is returnedinto the patient's blood stream. Preferably, the blood is returned intothe patient's blood stream at the same place as at which it wasextracted, e.g., by way of a double-lumen venous catheter. In oneembodiment, the access line 1 may be color coded red, the return line 2may be color coded blue, and the filtrate connecting tubing 7 may becolor coded yellow.

Before the hemofiltered blood is returned to the patient, a substitutioninfusion fluid can be infused to the return line 2 of theextra-corporeal circuit. In one embodiment, a one-part substitutionfluid, stored in reservoir 11 of FIG. 1, may be an aqueous fluid forextra-corporeal treatments comprising (as used herein mmol/L is“millimoles” of the salt or ion per liter of aqueous substitutioninfusion fluid) between 0.2 and 1, preferably between 0.5 and 0.9 mmol/Lof dihydrogen phosphate ions; between 70 and 130, preferably between 90and 120 mmol/L of sodium ions; between 1.6 and 2.6, preferably between1.9 and 2.4 mmol/L of calcium ions; between 0.25 and 1.25, preferablybetween 0.5 and 1.0 mmol/L of magnesium ions; between 1 and 4,preferably between 1.8 and 3.5 mmol/L of potassium ions; between 2 and11.5, preferably between 5.5 and 7.5 mmol/L of glucose; below 5.5mmol/L, preferably between 0 and 3.1 mmol/L of acetate ions; and below5.5. mmol/L, preferably between 0 and 3.1 mmol/L of bicarbonate ions.This substitution infusion fluid is usually supplemented with chlorideions to achieve a neutral electrochemical balance.

In another embodiment, the one-part substitution infusion fluid may bean aqueous solution, preferably comprising about 117 mmol/L of sodiumions, about 2.5 mmol/L of potassium ions, about 0.83 mmol/L of phosphateions, about 2.3 mmol/L of calcium ions, about 0.89 mmol/L of magnesiumions, about 6.4 mmol/L of glucose, and less than about 3.1 mmol/L ofacetate ions, in the absence of bicarbonate ions, and supplemented withchloride ions to keep electrochemical balance.

As shown in FIG. 2, the substitution infusion fluid may be infused tothe return line 2 of the extra-corporeal circuit, post-bubble air trap3, at connection 44. Another substitution solution may be infused to thereturn line 2 of the extra-corporeal circuit, post-bubble air trap 3, atconnection 46. A two-part aqueous substitution infusion fluid made inaccordance with the teachings of the invention may include a firstaqueous substitution infusion fluid comprising from about 70 mmol/L toabout 130 mmol/L of sodium ion, from about 0.01 mmol/L to about 5 mmol/Lof potassium ion, from about 100 mmol/L to about 150 mmol/L of chlorideion, from about 0.01 mmol/L to about 1.5 mmol/L of phosphate ion and,optionally, from about 2 mmol/L to about 11.5 mmol/L of glucose.

The first substitution infusion fluid described above could then be usedin combination with a second aqueous infusion fluid comprising fromabout 10 mmol/L to about 35 mmol/L of calcium ion, from about 2.5 mmol/Lto about 20 mmol/L of magnesium ion and, optionally, from about 30mmol/L to about 100 mmol/L of any one or more of sulphate, gluconate,glubionate or chloride ion.

Both the one-part and the two-part substitution infusion fluids may beused with a matching citrate solution. The same citrate solution may beused regardless of whether a one part or two-part substitution infusionfluid is used. Thus by using the specific substitution infusion fluidtogether with a matching citrate anticoagulant solution in anextracorporeal blood treatment procedure, the concentrations ofpotassium, phosphate, calcium, magnesium, bicarbonate ions, and glucoseremain substantially within acceptable ranges. In most cases, theconcentrations of these ions and glucose remain more or less constant inthe systemic blood of the patient undergoing, for example,hemofiltration. Consequently, the chances of the occurrence of theproblems encountered in hemofiltration to date are significantlyreduced, if not eliminated altogether. Particularly, the chances of theabove-indicated complications including electrolyte or acid-baseabnormalities and/or severe bleeding are significantly reduced.

The substitution infusion fluids, according to the invention, may beconveniently prepared by dissolving salts in water in such amounts thatthe desired concentrations are reached, as is well within the expertiseof the normal person skilled in the art. During preparation, it. isdesired that a sterile environment is maintained. Accordingly, thesubstitution infusion fluids preferably are sterile, according to theEuropean Pharmacopeia or United States (US) Pharmacopeia, therebyavoiding the risk of infections in a patient when the fluids are usedduring hemofiltration.

Typically, substitution infusion fluids are hypotonic. Exemplary valuesare between 200 and 270 mOsm/L. Nevertheless, it has been found that thefluid is well tolerated by patients when it is used in a hemofiltrationprocedure. It has been found that the hypotonicity is in fact beneficialby compensating for the hypertonicity induced at the arterial side ofthe extracorporeal circuit by the anticoagulant. The result is that theblood that is returned into the patient's blood stream has substantiallynormal (physiological) osmolarity.

It has been found that when a two-part substitution infusion fluid ofthis type is used in combination with a matching solution of trisodiumcitrate comprising, for example, of about 106-300 mmol/L trisodiumcitrate as an anticoagulant, the concentrations of the indicated ions inthe patient's blood remain substantially within the physiological rangethroughout the pure hemofiltration procedure.

In one preferred embodiment, the present citrate anticoagulationsolution, for example, for pure hemofiltration treatment is an aqueoussolution meeting the above requirements, comprising about 38-39 mmol/Lof citric acid and about 211-212 mmol/L of trisodium citrate. Thiscitrate anticoagulation solution is preferably used in combination witha matching two part substitution infusion fluid as disclosed above.

By using the citrate anticoagulation infusion fluid according to theinvention in an extracorporeal treatment, the blood is effectivelyanticoagulated within the extracorporeal circuit and not within thesystemic circulation of the patient and the concentrations of sodium,potassium, calcium, magnesium, and bicarbonate ions remain substantiallywithin ranges of which it is accepted that they do not lead tounacceptable risk of complications within the patient. This citrateanticoagulant solution can be used in any appropriate extracorporealblood treatment and is especially useful during all kinds of purehemofiltration procedures in combination with the matching substitutioninfusion fluids according to the invention.

In another embodiment of the invention, the two-part substitutioninfusion fluid is used in combination with the matching citratesolution. Such two-part substitution infusion fluid for use in variousextracorporeal treatments will comprise a first infusion substitutionfluid including electrolytes, but excluding calcium and magnesium, and asecond infusion fluid comprising calcium and magnesium. In one preferredexample, the two part substitution infusion fluid may comprise a firstsubstitution infusion fluid comprising between about 117 and about 129mmol/L of sodium, between about 2.5 and about 3.0 mmol/L of potassium,between about 115 and about 140 mmol/L of chloride and between about 0.7and about 0.9 mmol/L of phosphate; and a second substitution infusionfluid may comprise between about 15 and about 25 mmol/L of calcium andbetween about 10 and about 12 mmol/L of magnesium ions. Optionally, thefirst substitution infusion fluid may also comprise between about 6.5and about 7.1 mmol/L of glucose. In other embodiments, between 0.4 and0.8 mmol/L of phosphate ions may be added to either the first of thesecond solution.

In one embodiment, calcium ion provided in the form of a calcium saltselected from the group comprising calcium glubionate, calcium chlorideand calcium gluconate and magnesium ion is provided in the form of amagnesium salt selected from the group comprising magnesium sulfate,magnesium chloride, magnesium glubionate and magnesium gluconate.

In yet another preferred embodiment the two-part substitution infusionfluid comprises a first substitution infusion fluid comprising about 117to about 118 mmol/L of sodium, about 6.5 to about 6.8 mmol/L of glucose,about 2.6 to about 2.8 mmol/L of potassium, about 115 mmol/L to about140 mmol/L of chloride and about 0.8 mmol/L phosphate; and a secondsubstitution infusion fluid comprising about 15 to about 24 mmol/L ofcalcium and from about 10 to about 15.5 mmol/L of magnesium ions. In afurther preferred embodiment, the first substitution infusion fluid maycomprise about 118-119 mmol/L of chloride ion. In yet another preferredembodiment, the second infusion fluid may comprise about 24 mmol/L ofcalcium and about 10.8 mmol/L of magnesium.

As shown in FIG. 4, the substitution infusion fluid may be infused tothe return line 2 of the extra-corporeal circuit, pre-bubble air trap 3,at connection 38 (if the calcium ions and the magnesium ions are notpresent in the substitution infusion fluid) or post-bubble air trap 3 atconnection 44 but before air detection system 33. In CVVH, thesubstitution infusion fluid may also be infused to the access line 1 ofthe extra-corporeal circuit, post-blood pump 14, at inlet port 10 orpre-blood pump 14 at inlet port 32. For CVVHD and CVVHDF, thesubstitution infusion fluid may be pumped to the inlet dialysate port 18of the artificial kidney 60 via a dialysate line (not shown). Thedialysate line can be pre-connected or removeably engageable with theartificial kidney 60 using couplers, such as male and female Luer-lockconnectors. The dialysate line may be color coded purple.

The substitution infusion fluid (without the calcium ions and themagnesium ions) for CVVHDF can also be infused to the return line 2 ofthe extra-corporeal circuit pre-bubble air trap 3 at connection 38 orpost-bubble air trap 3 at connection 44 but before an air detectionsystem 33. It is understood to a person skilled in the art that thesubstitution infusion fluid can be infused to the access line inconjunction with the return line. Some of the embodiments utilize asubstitution infusion fluid that does not contain calcium and magnesiumions.

The substitution infusion fluid can be added from the reservoir 11, viaa pump 12 and a heater 13. The heater 13 ensures that the substitutioninfusion fluid ultimately entering the patient's body is substantiallyequal to the patient's body temperature, thus making the entireprocedure substantially less uncomfortable. In one embodiment, apressure monitoring system, shown in FIG. 4 as 20, is connected to thereturn line 2 to control pressurization of tubing segment containingblood re-infused to the patient. In addition, an air detection system 33can be used on the return line 2 to detect any air bubbles that may havebeen introduced with the substitution infusion fluid.

FIG. 2 depicts an embodiment wherein the two-part substitution infusionis provided with two reservoirs 11 and 15 that supply the firstsubstitution infusion fluid and the second substitution infusion fluid,respectively, via separate pumps 12 and 16 and heaters 13 and 17. If thevolume of the calcium/magnesium substitution infusion fluid isrelatively small, then it may not be necessary to heat such substitutioninfusion fluid and, therefore, the second heater 17 may be optional. Theflow or volume of the supplied substitution infusion fluid may becontrolled by connectors 44 and 46. Connectors 44 and 46 may have aclosing system, such as a valve, a mechanical clamp, or Luer-lockconnectors. These connectors 44 and 46 are preferably coupled to thereturn line 2 prior to the connection of the air detection system(device not shown in FIG. 2). The second substitution infusion fluidline can be color coded white.

In one embodiment, the substitution infusion fluid or a mixturecontaining the retentate blood with the substitution infusion fluid,passes through a drip chamber or air detection system, shown in FIG. 4as 33, before flowing back to the patient via the return line 2. Anautomatic return line clamp 39 is preferably used post air detectionsystem 33 in order to automatically close return line 2 in case of airdetection or return line 2 disconnection from catheter return waydetected by a low return pressure value.

During the procedure, the amount of filtrate collected in the collectionreservoir 9 is determined accurately, e.g., by weighing. The amount ofsubstitution infusion fluid added to the blood is adapted to thisamount. This makes it possible to make sure that an exactlypredetermined volume of fluid is returned to the patient's body,matching the originally extracted volume therefrom or adapted to thefluid balance needed in a particular patient. The flow through pumps 8and 12, or 8 and 16, or 8, 12 and 16, are accordingly precisely adjustedto one another. Typically, the substitution infusion fluid isadministered (infused) into the blood at a rate of between about 1 and80 ml/min per 200 ml/min blood. In practice, alerting means, such as anaudible alarm, are often provided for alerting nursing personnel shouldan interruption of the blood, filtrate, or substitution flow occur.Typically, said specific anticoagulation fluid of trisodium citrate andcitric acid is infused into the blood at a rate of between about 1.3 and4 ml/min per 200 ml/min blood.

FIG. 3 illustrates another hemofiltration process according to oneembodiment of the invention. In this embodiment, the substitutioninfusion fluid can be introduced to the access line 1 of theextra-corporeal circuit via a pre-dilution line 31 and to the returnline 2 of the extra-corporeal circuit via a post-dilution line 52. Apre-dilution pump 23, also shown in FIG. 4, pumps the first substitutioninfusion fluid from the reservoir 11 to the pre-dilution line 31.Furthermore, a post-dilution pump 50, also referred to herein as firstpost-dilution pump 50, pumps the first substitution infusion fluid fromthe reservoir 11 to the post-dilution line 52. In this embodiment, thesubstitution infusion fluid does not include calcium and magnesium ions.

FIG. 4 shows a heating system 34 coupled to the dilation lines 31 and52. The heating system 34 preferably contains a chamber 37 where gas canbe removed from fluid before infusing to the extra-corporal circuit andwhere temperature of fluid is controlled. This degassing chamber 37contains first and second infusion ports with a closing system, such asa valve, a mechanical clamp or Luer-lock connectors. The closing systemis preferably used before the heating system 34.

In one embodiment, a pumping system (device not shown) is used to removegas from the degassing chamber 37 during priming and treatment. Theheating system 34 may also be coupled to a temperature sensor 58 inorder to regulate and control the temperature of the heated fluid. Inaddition, a serial tubing 56 can be used to send substitution infusionfluids to post-dilution line 52, pre-dilution line 31 and/or dialysateline (not shown).

FIGS. 3 and 4 show the pre-dilution line 31 connected to the access line1 post-blood pump 14. In one embodiment, the pre-dilution line 31 isconnected to the access line 1 pre-blood pump 14. The pre-dilution line31 can be pre-connected or removeably engageable with couplers on accessline 1. FIG. 4 also shows the post-dilution line 52 can be connected tothe return line 2 pre-air trap 3. In one embodiment, the post-dilutionline 52 is connected to the return line 2 post-air trap 3. Likewise, thepost-dilution line 52 can be pre-connected or removeably engageable withcouplers on return line 2. In addition, the pre-dilution line 31 andpost-dilution line 52 may have one or more connectors, such as Luer-lockconnectors, to couple one or more reservoirs 11 of the substitutioninfusion fluid. Pre-dilution line 31 and post-dilution line 52 may becolor coded green.

FIG. 5 illustrates an extracorporeal blood treatment system with amonitoring system 65, according to one embodiment of the invention. Themonitoring system 65 can have sensor indicators to notify the user onthe status of the extracorporeal blood treatment system. The monitoringsystem 65 can also facilitate control of the extracorporeal bloodtreatment system, including but not limited to, a blood pump 14, afiltrate pump 8, a first post-dilution pump 50, a pre-dilution pump 23,a dialysate pump (device not shown), an anticoagulant pump 24, a secondpost-dilution pump 16, and a scale system 67. The monitoring system 65can provide a user friendly interface to allow for therapies, such asbut not limited to, CVVH, CVVHD, and CVVHDF. The monitoring system 65can also provide control of the heating system 34, blood leakagedetector 36, and air bubble detector 33. Furthermore, the monitoringsystem 65 can also have indicators for pressure sensors 19, 20, 21 and22.

The pumps utilized in the extracorporeal blood treatment system arethose typically used in the industry, such as pulsed motor pumps andstep motor pumps. The pulsed increase or the number of steps for oneunit of blood flow rate (1 ml/min) increase can be defined during acalibration process. The blood pump 14 preferably maintains a blood flowrate between about 10 ml/min (“MinBFR”) and about 500 ml/min (“MaxBFR”).The filtrate pump 8 preferably maintains a filtrate flow less than about14,000 ml/h. The pre-dilution pump 23, the post-dilution pump 50, andthe dialysate pump (device not shown), preferably maintain a flow rateless than about 10,000 ml/h. The anticoagulant pump 24 and the secondpost-dilution pump preferably maintain a flow rate less than about 1000ml/h. The solution compositions and the flow rates described herein areexamples are not intended to limit the scope of the invention.

In one embodiment, if the pre-dilution, post-dilution and dialysatesolutions are the same solution and connected to the same substitutiontubing 56, then their respective pumps 50, 23 and 24 can be regulatedand controlled together.

Since the infusion of all fluids are regulated and controlled together,when the blood pump 14 is running, all other pumps must be activated.However, when one of the pumps halts for any reason, the other pumps mayalso stop pumping. Unfortunately, when the blood pump 14 stops, there isa risk of blood clotting inside the return line 2. Since the access line1 of the extra-corporal circuit has citrate in it, the risk of clottinginside this part is low. Therefore, when one pump halts for any reason,the stops of blood pump 14 and anticoagulant pump 24 are preferablydelayed by, for example, about 10 seconds after the other pumps havealready stopped. This allows the return line 2 and return catheter wayto fill with blood containing citrate and avoid clotting during thehalting of the blood pump 14. This may require an algorithm referred toherein as “Stop Blood Pump Program.”

A scale system 67 may be configured to accept the handling of more thanone reservoir; preferably four reservoirs 25, 9, 11, and 15. If thescale 67 is configured to handle these reservoirs, then the maximumoverloaded weight will be greater than about 24 kg. In one embodiment,the scale system 67 is configured to handle more than one reservoir 25,more than one reservoir 9, more than one reservoir 11, and more than onereservoir 15. The scale system 67 preferably has a gauge constraint unit(device not shown) to aid in controlling and regulating the pumps' flowrate.

FIG. 6 illustrates a simplified block diagram of a control system 70that regulates, controls, and monitors the operations of theextracorporeal blood treatment system. The control system 70 may includeone or more processing units (e.g., a master processing unit 72 and acontroller 74). The control system 70 may also include a masterextension 76 and a controller extension 78. The master extension 76monitors the feedback data (pump and scale data) for the masterprocessing unit 72 and dictates the flow rate of the citrate and calciumpumps depending on the scale data (citrate and calcium scale) and theprogramming values from the master processing unit 72. The controllerextension 78 retrieves the encoder data from the citrate and calciumpumps and monitors the adequate flow rate. In the case of a deviationbetween the received value and the set parameters, the controllerextension 78 is able to stop the citrate and calcium pumps. This datafrom the protective subsystem are sent to the controller 74. Moreover,the controller extension 78 receives data from the controller 74.

All controls and monitoring are performed electronically using computeralgorithms. When programming a treatment, filtrate flow rate is linkedto programming values for post-dilution flow rate, pre-dilution flowrate, dialysate flow rate, anticoagulant flow rate, second substitutioninfusion fluid flow rate, and fluid loss rate. The relationship betweenthe flow rates is: the filtrate flow rate equals the sum ofpost-dilution flow rate, pre-dilution flow rate, dialysate flow rate,anticoagulant flow rate, second substitution solution flow rate, andfluid loss rate.

When the citrate anticoagulant solution is added to the blood, calciumions are fixed by citrate molecules or metabolized by a patient's liverand muscles such that calcium ions are released to the blood and citratemolecules are converted into bicarbonate molecules. The kinetics forliver and muscles metabolism take time to be efficient, and therefore,to avoid Calcium/citrate molecules accumulation or metabolic acidosisduring first minutes of treatment, another algorithm can be used inorder to increase progressively working flow rates to the programmingflow rates during the first minutes of treatment.

This algorithm used in increasing progressively working flow ratesutilizes a Ratio (R) that depends on programming blood flow rate, and afrequency value (1/T). Blood flow rate starts with MinBFR and isincreased each time T interval from a fixed value (1 per 1 ml/min or 10per 10 ml/min). Ratio R is calculated by dividing the working blood flowrate by the programming blood flow rate. At each time T interval, allworking flow rates (post-dilution, pre-dilution, dialysate, filtrate,anticoagulant, and second substitution infusion fluid flow rates) aremodified such that the working flow rate equals Ratio R multiplied byprogramming flow rate. This time T for progressive increase of workingflow rates is referred to as “Regulated Start Mode.” The Regulated StartMode is automatically achieved once the working blood flow rate reachesthe programming flow rate value.

When pre-dilution substitution infusion fluid is infused pre-blood pump14 and/or anticoagulant (citrate) solution is infused pre-blood pump 14,the real working blood flow rate is equal to the sum of programmingblood flow rate, pre-dilution flow rate, and anticoagulant (citrate)flow rate.

When citrate molecules for anticoagulant are included into asubstitution infusion fluid used as pre-dilution solution, theanticoagulant (citrate) flow rate can be programmed to 0 ml/h. Whencalcium and magnesium ions are included into a substitution infusionfluid used as post-dilution solution, the second solution containingcalcium and magnesium ions may not be necessary, and therefore, the flowrate of the second substitution infusion fluid can be programmed to 0ml/h.

In one embodiment, the extracorporeal blood treatment system may includea heparin pump system (device not shown) in order to keep thepossibility of using heparin as anticoagulant when patient metabolismcannot allow the citrate anticoagulant process. When a patient'smetabolism cannot allow use of a citrate anticoagulant process,anticoagulant (citrate) flow rate can be programmed to 0 ml/h and thesecond substitution infusion fluid (Calcium/Magnesium solution) flowrate can be programmed to 0 ml/h.

In another embodiment, the extracorporeal blood treatment system maycontain an algorithm to control the Trans-Membrane Pressure (TMP) as amathematical relation between return pressure 20, pre-filter pressure 21and filtrate pressure 22. According to this relationship, TMP is equalto the sum of return pressure 20 with pre-filter pressure 21 divided by2 and subtracted by the filtrate pressure 22. The extra-corporal bloodtreatment system also contains an algorithm to control the Pressure Drop(PD) through blood compartment 4 of the artificial kidney 60 as amathematical relation between return pressure 20 and pre-filter pressure21. According to this relationship, PD is equal to the pre-filterpressure 21 minus return pressure 20 plus a Correcting Factor (CF),where CF is evaluated by the difference of positioning level between thereturn pressure sensor 20 and the pressure sensor 21.

Those skilled in the art will appreciate that the various illustrativelogical components, blocks, modules, circuits, and algorithms describedin connection with the embodiments disclosed herein may be implementedas electronic hardware, computer software, or combinations of both. Toillustrate this interchangeability of hardware and software, variousillustrative components, blocks, modules, circuits, and algorithms havebeen described above generally in terms of their functionality. Whethersuch functionality is implemented as hardware or software depends uponthe particular application and design constraints imposed on the overallsystem. Skilled artisans may implement the described functionality invarying ways for each particular application, but such implementationdecisions should not be interpreted as causing a departure from thescope of the present disclosure.

The various illustrative logical blocks, modules, and circuits describedin connection with the embodiments disclosed herein may be implementedor performed with a general purpose processing device, a digital signalprocessing device (DSP), an application specific integrated circuit(ASIC), a field programmable gate array (FPGA) or other programmablelogic device, discrete gate or transistor logic, discrete hardwarecomponents, or any combination thereof designed to perform the functionsdescribed herein. A general purpose processing device may be amicroprocessing device, but in the alternative, the processing devicemay be any conventional processing device, processing device,microprocessing device, or state machine. A processing device may alsobe implemented as a combination of computing devices, e.g., acombination of a DSP and a microprocessing device, a plurality ofmicroprocessing devices, one or more microprocessing devices inconjunction with a DSP core or any other such configuration.

The methods or algorithms described in connection with the embodimentsdisclosed herein may be embodied directly in hardware, software, orcombination thereof. In software the methods or algorithms may beembodied in one or more instructions that may be executed by aprocessing device. The instructions may reside in RAM memory, flashmemory, ROM memory, EPROM memory, EEPROM memory, registers, hard disk, aremovable disk, a CD-ROM, or any other form of storage medium known inthe art. An exemplary storage medium is coupled to the processing devicesuch the processing device can read information from, and writeinformation to, the storage medium. In the alternative, the storagemedium may be integral to the processing device. The processing deviceand the storage medium may reside in an ASIC. The ASIC may reside in auser terminal. In the alternative, the processing device and the storagemedium may reside as discrete components in a user terminal.

While certain exemplary embodiments have been described and shown in theaccompanying drawings, it is to be understood that such embodiments aremerely illustrative of and not restrictive on the broad invention, andthat this invention not be limited to the specific constructions andarrangements shown and described, since various other changes,combinations, omissions, modifications and substitutions, in addition tothose set forth in the above paragraphs, are possible. Those skilled inthe art will appreciate that various adaptations and modifications ofthe just described preferred embodiment can be configured withoutdeparting from the scope and spirit of the invention. Therefore, it isto be understood that, within the scope of the appended claims, theinvention may be practiced other than as specifically described herein.

The invention claimed is:
 1. A machine-readable medium embodyinginstructions that may be performed by one or more processors, theinstructions comprising: instructions for pumping blood from a patient'sblood stream into an access line; instructions for introducing ananticoagulant solution into the pumped blood; instructions for filteringthe pumped blood; instructions for delivering the pumped blood from thefiltering step to a return line; instructions for introducing asubstitution fluid into the pumped blood; instructions for introducing acalcium and magnesium solution into the blood traveling through thereturn line; and instructions for returning the blood back to thepatient's blood stream.
 2. The machine-readable medium of claim 1,wherein the substitution fluid is introduced into the access line. 3.The machine-readable medium of claim 1, wherein the substitution fluidis introduced into the return line.
 4. The machine-readable medium ofclaim 1, wherein the substitution fluid is introduced into the accessline and into the return line.
 5. The machine-readable medium of claim1, further comprising instructions for monitoring the blood pressure inthe access line.
 6. The machine-readable medium of claim 1, furthercomprising instructions for monitoring the blood pressure in the returnline.
 7. The machine-readable medium of claim 1, further comprising:instructions for exporting through a filtrate line a filtrate obtainedfrom the filtering step; and instructions for monitoring the pressure inthe filtrate line to control filtrate pressurization.
 8. Themachine-readable medium of claim 1, further comprising: instructions forexporting through a filtrate line a filtrate obtained from the filteringstep; and instructions for detecting blood leakage in the filtrate lineto control leakage of blood cells through the filter.
 9. Themachine-readable medium of claim 1, further comprising: instructions forexporting through a filtrate line a filtrate collected from thefiltering step; instructions for storing the filtrate traveling throughthe filtrate line in a reservoir; instructions for weighing the filtratestored in the reservoir; and instructions for computing the amount ofsubstitution fluid introduced in the blood from the weighing step. 10.The machine-readable medium of claim 1, further comprising: instructionsfor detecting air bubbles from the blood introduced with thesubstitution fluid; and instructions for removing air bubbles from theblood before it is returned into the patient's blood stream.
 11. Themachine-readable medium of claim 1, further comprising instructions forheating the substitution fluid introduced into the blood to atemperature substantially equal to the patient's body temperature.